Ito Sayaka, Yoshimoto Ryo, Miyamoto Yasuhisa, Mitobe Yuko, Nakamura Takao, Ishihara Akane, MacNeil Douglas J, Kanatani Akio, Tokita Shigeru
Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Tsukuba, Ibaraki 300-2611, Japan.
Eur J Pharmacol. 2006 Jan 4;529(1-3):40-6. doi: 10.1016/j.ejphar.2005.10.066. Epub 2005 Nov 28.
Histamine H(3) receptor antagonists are potential therapeutic agents for cognitive dysfunction, epilepsy, hypersomnia and obesity. GT-2331 (4-[(R,R)-2-(5,5-dimethyl-1-hexynyl)cyclopropyl]-1H-imidazole) was originally identified as a potent histamine H(3) receptor antagonist. However, recent reports demonstrated a complex pharmacology for GT-2331. To further understand the pharmacological profile of GT-2331, we characterized GT-2331 using various in vitro and in vivo assays. In vitro, GT-2331 behaved as a full agonist on adenylyl cyclase inhibition and as a partial agonist on [(35)S]GTPgammaS binding at the recombinant rat histamine H(3) receptor. In contrast, in vivo, GT-2331 had no effect on brain histamine turnover while the histamine H(3) receptor agonist R-alpha-methylhistamine significantly decreased histamine turnover. Furthermore, GT-2331 completely blocked R-alpha-methylhistamine-induced water intake, suggesting that GT-2331 behaves as a full antagonist. Thus, GT-2331 displayed the spectrum of pharmacological activities from full agonism to full antagonism, these observations suggest that histamine H(3) receptor ligands need to be carefully evaluated in various paradigms.
